Parathyroid hormone (hereinafter referred to as PTH) is a polypeptide hormone which is produced in the parathyroid gland and secreted therefrom. The main function of this hormone is to keep the calcium level in body fluids constant. PTH promotes bone resorption and calcium resorption in the kidney, thereby increasing the calcium level in blood, and PTH also promotes excretion of phosphate, thereby decreasing the phosphate level in blood. A decrease in the calcium level in blood promotes PTH secretion, while an increase in the calcium level in blood suppresses the secretion of PTH.
Hyperparathyroidism, which is characterized by excess secretion of PTH, includes primary and secondary hyperparathyroidism. In primary hyperparathyroidism, excess secretion of PTH due to tumefaction of the parathyroid gland, etc. results in dysbolism of calcium, thereby causing disorders such as hypercalcemia, hypophosphatemia, osteitis fibrosa, nephrolithiasis, and hypertension. Secondary hyperparathyroidism is caused when a low serum calcium level continues for a long time, which condition results from decreased renal function, deficiency of activated vitamin D, decreased reactivity of bones to PTH, etc. Secondary hyperparathyroidism results in an increase in PTH secretion. In some cases, this excess secretion of PTH continues even when the serum calcium level becomes normal or elevated, and may result in hyperparathyroidism becoming serious. For example, in a patient who is subjected to hemodialysis because of chronic renal failure, hyperparathyroidism tends to be serious. One of the important factors affecting this tendency is development of resistance to PTH, which is considered to be associated with reactivity to PTH. At present, secondary hyperparathyroidism is treated by the administration of activated vitamin D.sub.3.
The severity of secondary hyperparathyroidism in hemodialyzed patients varies among individuals, and therefore genomic factors have become of interest. As an example of studies on genomic factors, there is a report which shows the relationship in Japanese between polymorphism of the vitamin D receptor (VDR) gene by restriction enzyme Bsm I and the serum PTH level in hemodialyzed patients (Y. Tsukamoto et al., Nature Med. vol.2, 1996, p. 1162). Polymorphism of the VDR gene is correlated with occurrence of secondary hyperparathyroidism and response to treatment with vitamin D. Also, severity of primary hyperparathyroidism is thought to be associated with the same genomic factors in some cases.
With respect to the mechanism of occurrence of hyperparathyroidism, genetic differences in reactivity to PTH have been thought to be a stronger determining factor. However, a methodology has not been established for examining genetic polymorphism to predict reactivity to PTH.
Polymorphism of the parathyroid hormone receptor gene was reported by Frank G. Hustmyer et al. in Human Mol. Gent. vol. 2, p. 1330 (Bsm I polymorphism) and by E. Schipani et al in Human Mol. Gent. vol. 3, p. 1210 (polymorphism in exon M7). However, there is no report demonstrating the polymorphism associated with PTH reactivity.
As mentioned above, a method for predicting PTH reactivity by analysis of genetic polymorphism has not been found, PTH reactivity being thought to be associated with severity of hyperparathyroidism, and predicting the severity thereof was difficult. The prediction of the severity of hyperparathyroidism is advantageous. For example, if a tendency for secondary hyperparathyroidism observed in hemodialyzed patients to become serious is predicted, a suitable method for treatment can be selected so as to prevent it from becoming serious. Alternatively, if the severity of symptoms accompanied by primary hyperparathyroidism such as hypercalcemia, bone lesions, urinary calculus, etc. is predicted, it may be possible to determine whether an operation for removal of the parathyroid gland should be performed and to determine how urgent the operation is. Furthermore, the prediction of PTH reactivity is useful for predicting the effects of PTH administration in the treatment of regressive osteoporosis.